Apoptosis is a highly conserved cell suicide program essential for development and tissue homeostasis of all metazoan organisms. Changes to the apoptotic pathway that prevent or delay normal cell turnover can be just as important in the pathogenesis of diseases as are abnormalities in the regulation of the cell cycle. Like cell division, which is controlled through complex interactions between cell cycle regulatory proteins, apoptosis is similarly regulated under normal circumstances by the interaction of gene products that either prevent or induce cell death.
TNF-related apoptosis-inducing ligand (TRAIL, also referred to as Apo2L) is a member of the TNF cytokine family. Upon binding to DR4 or DR5, two members of the TNF receptor super family, TRAIL induces cell death by apoptosis. See, e.g., Pan et al., Science 277:815–8 (1997); Sheridan, et al., Science 277:818–21 3 (1997); Walczak et al, EMBO J. 16:5386–97 4 (1997). In vitro, TRAIL has been shown to kill tumor cells, but is relatively non-toxic to normal cells.
Additional therapies are needed to treat cancer. The present invention addresses this and other problems.